This proposal describes a 5 year training program for the development of an academic career in Laboratory Medicine. The principal investigator has completed structured residency training in Pathology at the University of Pennsylvania and now, will expand upon his scientific skills through an unique integration of interdepartmental resources. This program will promote the command of transcriptional corepressor biology, as applied to hematopoietic disease. Mitchell A. Lazar, MD, PhD will mentor the principal investigators scientific development. Dr. Lazar is a recognized leader in the field of transcriptional repression. He is the Chief of Endocrinology and has trained numerous postdoctoral fellows and graduate students. To enhance the training, the program will enlist the expertise of Warren S. Pear, MD, PhD, Assistant Professor of Pathology. Dr. Pear pioneered the ex vivo bone marrow transduction techniques that will be applied in the analyses of repression. In addition, an advisory committee of highly-regarded medical scientists will provide scientific and career advice. Research will focus on transcriptional repression in myeloid progenitor cells. Recent work in Dr. Lazar's laboratory demonstrated that aberrant recruitment of corepressors may underlie the disruption of myeloid development in leukemia associated with the AML1-ETO fusion protein. The proposed experiments will entail introduction of AML1-ETO and derivatives into mouse bone marrow and myeloid cell lines. Subsequently, phenotypes will be examined using an assortment of biochemical, molecular, and cellular techniques. The specific aims include: 1) Establishing an in vivo model for the analysis of interactions between AML1-ETO and repression pathways, 2) Determining if corepressor recruitment by AML1 is sufficient to exert the pathogenic effects of AML1-ETO, and 3) Determining the role of ETO domains in the disruption of myeloid development by AML1-ETO. This will be the first detailed functional analysis of the mechanisms of transcriptional repression by AML1-ETO using models that attempt to mimic the pathways of the myeloid progenitor. The Pathology department of the University of Pennsylvania provides an ideal setting for training physician-scientists by incorporating expertise from diverse resources into customized programs. Such an environment maximizes the potential for the principal investigator to establish a scientific niche from which an academic career can be constructed.